Apparatus and method for easing use of a spectrophotometric based noninvasive analyzer

ABSTRACT

A placement guide apparatus with an improved hydration inducing plug used in coupling a noninvasive analyzer to a sampling site to determine analyte in the human body is disclosed. The hydration inducing plug includes at least one fluoropolymer that may be used as a coupling agent. The guide apparatus may further include an automated or semi-automated coupling fluid delivery system. Use of either of these couplers mitigates issues associated with related technology and enhances noninvasive analyte measurements, such as a near-IR diffuse reflectance based noninvasive glucose concentration analyzer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/824,459, filed Apr. 13, 2004 now U.S. Pat. No.7,333,843, which claimsbenefits to the U.S. provisional patent application Ser. No. 60/463,616filed on 16 Apr. 2003, the contents of each of which are incorporatedherein in their entirety by this reference thereto.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates generally to the technology of noninvasive analytedetermination in the human body. More particularly, the inventionrelates to the use of a placement guide in conjunction with a diffusereflectance based near-IR glucose analyzer. The placement guide couplesto a glucose analyzer and has at least one of a hydration inducer and areservoir for a coupling agent used for automatic or manual delivery ofthe coupling agent to the sampling site.

2. Description of Related Art

Spectroscopy based noninvasive analyzers deliver external energy in theform of light or rays to a specific sampling site or region of the humanbody where the photons interact with the chemistry and physiology of thesampled tissue. A portion of the incident photons are scattered ortransmitted out of the body where they are detected. Based uponknowledge of the incident photons and detected photons, the chemicaland/or structural basis of the sampled site may be deduced. Severaldistinct advantages to a noninvasive system are the analyses of chemicaland structural constituents in the body without the generation of abiohazard in a pain free manner with limited consumables. The techniquemay also allow for multiple analytes or structural features to bedetermined at one time. Some common examples of noninvasive analyzersare magnetic resonance imaging (MRI), X-rays, pulse oximeters, andnoninvasive glucose analyzers. With the exception of X-rays, thesedeterminations are performed with relatively harmless wavelengths ofradiation. Examples herein focus on noninvasive glucose determination,but the principles apply to other modes of noninvasive analyses.

Diabetes

Diabetes is a chronic disease that results in improper production andutilization of insulin, a hormone that facilitates glucose uptake intocells. While a precise cause of diabetes is unknown, genetic factors,environmental factors, and obesity appear to play roles. Diabetics haveincreased risk in three broad categories: cardiovascular heart disease,retinopathy, and neuropathy. Diabetics may have one or more of thefollowing complications: heart disease and stroke, high blood pressure,kidney disease, neuropathy (nerve disease and amputations), retinopathy,diabetic ketoacidosis, skin conditions, gum disease, impotence, andfetal complications. Diabetes is a leading cause of death and disabilityworldwide. Moreover, diabetes is merely one among a group of disordersof glucose metabolism that also includes impaired glucose tolerance, andhyperinsulinemia, or hypoglycemia.

Diabetes Prevalence and Trends

Diabetes is an ever more common disease. The World Health Organization(WHO) estimates that diabetes currently afflicts 154 million peopleworldwide. There are 54 million people with diabetes living in developedcountries. The WHO estimates that the number of people with diabeteswill grow to 300 million by the year 2025. In the United States, 15.7million people or 5.9 percent of the population are estimated to havediabetes. Within the United States, the prevalence of adults diagnosedwith diabetes increased by 6% in 1999 and rose by 33% between 1990 and1998. This corresponds to approximately eight hundred thousand new casesevery year in America. The estimated total cost to the United Stateseconomy alone exceeds $90 billion per year. Diabetes Statistics,National Institutes of Health, Publication No. 98-3926, Bethesda, MD.(Nov. 1997).

Long-term clinical studies show that the onset of complications can besignificantly reduced through proper control of blood glucose levels.The Diabetes Control and Complications Trial Research Group, The effectof intensive treatment of diabetes on the development and progression oflong-term complications in insulin-dependent diabetes mellitus, N Eng Jof Med, 329:977-86 (1993); U.K. Prospective Diabetes Study (UKPDS)Group, Intensive blood-glucose control with sulphonylureas or insulincompared with conventional treatment and risk of complications inpatients with type 2 diabetes, Lancet, 352:837-853 (1998); and Y.Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y.Kojima, N. Furuyoshi, M. Shichizi, Intensive insulin therapy preventsthe progression of diabetic microvascular complications in Japanesepatients with non-insulin-dependent diabetes mellitus: a randomizedprospective 6-year study, Diabetes Res Clin Pract, 28:103-117 (1995).

A vital element of diabetes management is the self-monitoring of bloodglucose levels by diabetics in the home environment. However, currentmonitoring techniques discourage regular use due to the inconvenient andpainful nature of drawing blood through the skin prior to analysis. TheDiabetes Control and Complication Trial Research Group, supra. As aresult, noninvasive measurement of glucose has been identified as abeneficial development for the management of diabetes. Implantableglucose analyzers eventually coupled to an insulin delivery systemproviding an artificial pancreas are also being pursued.

Sampling Methodology

A wide range of technologies serve to analyze the chemical make-up ofthe body. These techniques may be broadly categorized into two groups,invasive and noninvasive. For the purposes of this document, atechnology that acquires any biosample from the body for analysis or ifany part of the measuring apparatus penetrates into the body, thetechnology is referred to as invasive.

-   -   Invasive: Some examples of invasive technologies for glucose        determination in the body are those that analyze the biosamples        of whole blood, serum, plasma, interstitial fluid, and mixtures        or selectively sampled components of the aforementioned.        Typically, these samples are analyzed with electrochemical,        electroenzymatic, and/or colorimetric approaches. For example,        enzymatic and calorimetric approaches may be used to determine        the glucose concentration in interstitial fluid samples.    -   Noninvasive: A number of approaches for determining the glucose        concentration in biosamples, have been developed that utilize        spectrophotometric technologies. These techniques include: Raman        and fluorescence, as well as techniques using light from the        ultraviolet through the infrared [ultraviolet (200 to 400 nm),        visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to        4000 cm⁻¹), and infrared (2500 to 14,285 nm or 4000 to 700        cm⁻¹)].        Noninvasive Glucose Determination

There exist a number of noninvasive approaches for glucosedetermination. These approaches vary widely, but have at least twocommon steps. First, an apparatus is utilized to acquire a signal fromthe body without obtaining a biological sample. Second, an algorithm isutilized to convert this signal into a glucose determination.

One type of noninvasive glucose determination is based upon spectra.Typically, a noninvasive apparatus utilizes some form of spectroscopy toacquire the signal or spectrum from the body. Utilized spectroscopictechniques include, but are not limited to: Raman and fluorescence, aswell as techniques using light from ultraviolet through the infrared[ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to2500 nm or 14,286 to 4000 cm⁻¹), and infrared (2500 to 14,285 nm or 4000to 700 cm⁻¹)]. A particular range for noninvasive glucose determinationin diffuse reflectance mode is about 1100 to 2500 nm or ranges therein.K. Hazen, Glucose Determination in Biological Matrices UsingNear-infrared Spectroscopy, doctoral dissertation, University of Iowa(1995). It is important to note that these techniques are distinct fromthe traditional invasive and alternative invasive techniques listedabove in that the interrogated sample is a portion of the human bodyin-situ, not a biological sample acquired from the human body.

Typically, three modes are utilized to collect noninvasive scans:transmittance, transflectance, and/or diffuse reflectance. For examplethe signal collected, typically being light or a spectrum, may betransmitting through a region of the body such as a fingertip, diffuselyreflected, or transflected. Transflected here refers to collection ofthe signal not at the incident point or area (diffuse reflectance), andnot at the opposite side of the sample (transmittance), but rather atsome point on the body between the transmitted and diffuse reflectancecollection area. For example, transflected light enters the fingertip orforearm in one region and exits in another region typically 0.2 to 5 mmor more away depending on the wavelength utilized. Thus, light that isstrongly absorbed by the body such as light near water absorbance maximaat 1450 or 1950 nm would need to be collected after a small radialdivergence and light that is less absorbed such as light near waterabsorbance minima at 1300, 1600, or 2250 nm may be collected at greaterradial or transflected distances from the incident photons.

Noninvasive techniques are not limited to using the fingertip as ameasurement site. Alternative sites for taking noninvasive measurementsinclude: a hand, finger, palmar region, base of thumb, wrist, dorsalaspect of the wrist, forearm, volar aspect of the forearm, dorsal aspectof the forearm, upper arm, head, earlobe, eye, tongue, chest, torso,abdominal region, thigh, calf, foot, plantar region, and toe. It isimportant to note that noninvasive techniques do not have to be basedupon spectroscopy. For example, a bioimpedence meter would be considereda noninvasive device. Within the context of the invention, any devicethat reads a signal from the body without penetrating the skin andcollecting a biological sample is referred to as a noninvasive glucoseanalyzer. For example, a bioimpedence meter is a noninvasive device.

Calibration

Glucose analyzers require calibration. This is true for all types ofglucose analyzers such as traditional invasive, alternative invasive,noninvasive, and implantable analyzers. One fact associated withnoninvasive glucose analyzers is that they are secondary in nature, thatis, they do not measure blood glucose levels directly. This means that aprimary method is required to calibrate these devices to measure bloodglucose levels properly. Many methods of calibration exist.

One noninvasive technology, near-infrared spectroscopy, requires that amathematical relationship between an in vivo near-infrared measurementand the actual blood glucose value be developed. This is achievedthrough the collection of in-vivo NIR measurements with correspondingblood glucose values that have been obtained directly through the use ofmeasurement tools like a HEMOCUE or a YSI (YSI INCORPORATED, YellowSprings Ohio), or any appropriate and accurate traditional invasivereference device.

For spectrophotometric based analyzers, there are several univariate andmultivariate methods that may be utilized to develop the mathematicalrelationship between the measured signal and the actual blood glucosevalue. However, the basic equation being solved is known as theBeer-Lambert Law. This law states that the strength of anabsorbance/reflectance measurement is proportional to the concentrationof the analyte which is being measured, as in equation 1,A=εbC  (1)where A is the absorbance/reflectance measurement at a given wavelengthof light, ε is the molar absorptivity associated with the molecule ofinterest at the same given wavelength, b is the distance that the lighttravels, and C is the concentration of the molecule of interest(glucose).

Chemometric calibration techniques extract the glucose signal from themeasured spectrum through various methods of signal processing andcalibration including one or more mathematical models. The models aredeveloped through the process of calibration on the basis of anexemplary set of spectral measurements known as the calibration set andassociated set of reference blood glucose concentrations based upon ananalysis of capillary blood or venous blood. Common multivariateapproaches requiring an exemplary reference glucose concentration vectorfor each sample spectrum in a calibration include partial least squares(PLS) and principal component regression (PCR). Many additional forms ofcalibration are known, such as neural networks.

There are a number of reports on noninvasive glucose technologies. Someof these relate to general instrumentation configurations required fornoninvasive glucose determination. Others refer to samplingtechnologies. Those most related to the present invention are brieflyreviewed here:

As outlined above, there have been a number of studies documenting theneed for an accurate and precise noninvasive glucose analyzer.

R. Barnes, J. Brasch, D. Purdy, W. Lougheed, Non-invasive determinationof analyte concentration in body of mammals, U.S. Pat. No. 5,379,764(Jan. 10, 1995) describe a noninvasive glucose analyzer that utilizesdata pretreatment in conjunction with a multivariate analysis todetermine blood glucose concentrations.

General Instrumentation:

P. Rolfe, Investigating substances in a patient's bloodstream, UK PatentApplication No. 2,033,575 (Aug. 24, 1979) describe an apparatus fordirecting light into the body, detecting attenuated backscattered light,and utilizing the collected signal to determine glucose concentrationsin or near the bloodstream.

C. Dahne, D. Gross, Spectrophotometric method and apparatus for thenon-invasive, U.S. Pat. No. 4,655,225 (Apr. 7, 1987) describe a methodand apparatus for directing light into a patient's body, collectingtransmitted or backscattered light, and determining glucose fromselected near-IR wavelength bands. Wavelengths include 1560 to 1590,1750 to 1780, 2085 to 2115, and 2255 to 2285 nm with at least oneadditional reference signal from 1000 to 2700 nm.

M. Robinson, K. Ward, R. Eaton, D. Haaland, Method and apparatus fordetermining the similarity of a biological analyte from a modelconstructed from known biological fluids, U.S. Pat. No. 4,975,581 (Dec.4, 1990) describe a method and apparatus for measuring a concentrationof a biological analyte such as glucose using infrared spectroscopy inconjunction with a multivariate model. The multivariate model isconstructed form plural known biological fluid samples.

J. Hall, T. Cadell, Method and device for measuring concentration levelsof blood constituents non-invasively, U.S. Pat. No. 5,361,758 (Nov. 8,1994) describe a noninvasive device and method for determining analyteconcentrations within a living subject utilizing polychromatic light, awavelength separation device, and an array detector. The apparatusutilizes a receptor shaped to accept a fingertip with means for blockingextraneous light.

S. Malin, G Khalil, Method and apparatus for multi-spectral analysis oforganic blood analytes in noninvasive infrared spectroscopy, U.S. Pat.No. 6,040,578 Mar. 21, 2000) describe a method and apparatus fordetermination of an organic blood analyte using multi-spectral analysisin the near-IR. A plurality distinct nonoverlapping regions ofwavelengths are incident upon a sample surface, diffusely reflectedradiation is collected, and the analyte concentration is determined viachemometric techniques.

Specular Reflectance:

R. Messerschmidt, D Sting Blocker device for eliminating specularreflectance from a diffuse reflectance spectrum, U.S. Pat. No. 4,661,706(Apr. 28, 1987) describe a reduction of specular reflectance by amechanical device. A blade-like device “skims” the specular light beforeit can impinge on the detector. A disadvantage of this system is that itdoes not efficiently collect diffusely reflected light and the alignmentis problematic.

R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus,U.S. Pat. No. 5,636,633 (Jun. 10, 1997) describe a specular controldevice for diffuse reflectance spectroscopy utilizing a group ofreflecting and open sections.

R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus,U.S. Pat. No. 5,935,062 (Aug. 10, 1999) and R. Messerschmidt, M.Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No.6,230,034 (May 8, 2001) describe a diffuse reflectance control devicethat can discriminate between diffusely reflected light that isreflected from selected depths. This control device may additionally actas a blocker to prevent specularly reflected light from reaching thedetector.

Malin et. al., supra describe the utilization of specularly reflectedlight in regions of high water absorbance such as 1450 and 1900 nm tomark the presence of outlier spectra wherein the specularly reflectedlight is not sufficiently reduced.

K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method forreproducibly modifying localized absorption and scattering coefficientsat a tissue measurement site during optical sampling, U.S. Pat. No.6,534,012 (Mar. 18, 2003) describe a mechanical device for applyingsufficient and reproducible contact of the apparatus to the samplingmedium to minimize specular reflectance. Further the apparatus allowsfor reproducible applied pressure to the sampling site and reproducibletemperature at the sampling site.

Temperature:

It is well known that many physiological constituents have near-IRabsorbance spectra that are sensitive in terms of magnitude and locationto localized temperature. This has been reported as impactingnoninvasive glucose determinations. Hazen, et. al., supra.

Coupling Fluid:

Index of fraction matching between the sampling apparatus and sampledmedium is well known. Glycerol is a common index matching fluid foroptics to skin. A number of patents disclose more specific couplingfluids with important sampling parameters.

R. Messerschmidt, Method for non-invasive blood analyte measurement withimproved optical interface, U.S. Pat. No. 5,655,530 (Aug. 12, 1997), andR. Messerschmidt Method for non-invasive blood analyte measurement withimproved optical interface, U.S. Pat. No. 5,823,951 describe anindex-matching medium for use between a sensor probe and the skinsurface. The index-matching medium is a composition containingperfluorocarbons and chlorofluorocarbons.

M. Robinson, R. Messerschmidt, Method for non-invasive blood analytemeasurement with improved optical interface, U.S. Pat. No. 6,152,876(Nov. 28, 2000) and M. Rohrscheib, C. Gardner, M. Robinson, Method andapparatus for non-invasive blood analyte measurement with fluidcompartment equilibration, U.S. Pat. No. 6,240,306 (May 29, 2001)describe an index-matching medium to improve the interface between thesensor probe and skin surface during spectroscopic analysis. Theindex-matching medium is preferably a composition containingchlorofluorocarbons. The composition can also contain perfluorocarbons.

T. Blank, G. Acosta, M. Mattu, S. Monfre, Fiber optic probe guideplacement guide, U.S. Pat. No. 6,415,167 (Jul. 2, 2002) describe acoupling fluid of one or more perfluoro compounds where a quantity ofthe coupling fluid is placed at an interface of the optical probe andmeasurement site. Notably, perfluoro compounds do not have the toxicityassociated with chlorofluorocarbons.

Guide:

Blank et. al., supra describe the utilization of a guide in conjunctionwith a noninvasive glucose analyzer in order to increase precision ofthe location of the sampled site resulting in increased accuracy andprecision in a noninvasive glucose determination.

In all of the related technology of this section, no suggestion ofautomated analysis is made. Further, no suggestion is made for afluoropolymer hydration inducer or for a coupling fluid reservoir withinthe guide. Both of these guide features ease the use of a bioanalyzersuch as a near-IR based noninvasive glucose analyzer. In addition, todate no FDA device has been approved for the utilization by anindividual or a medical professional for noninvasive glucoseconcentration determination.

The Problem

Noninvasive glucose analyzers reported to date generally requireprecision in sampling in order to accurately determine glucoseconcentrations in the body. The measurement is complicated by everymanual step required in the spectral acquisition process utilized in agiven glucose determination. Complications include any of a requirementof time, a step requiring manual dexterity, or movement of measurementapparatus that may be bulky, fragile, or sensitive in terms of returnedanalytical signal. Elimination or automation of steps required for anoninvasive glucose determination is beneficial for at least one ofincreasing marketability of the analyzer, increasing the number ofpeople who may utilize the analyzer, reduction in time requirementsassociated with a glucose determination, and increased precision and/oraccuracy of a glucose determination. Specifically, preparation of thesampling site in terms of temperature, historesis of applied pressure,hydration, and optical scattering parameters involving actions from theuser that may be any of technically challenging, time consuming, anderror inducing.

What is desired is a mechanism for reducing user input through methodsand apparatus such as a hydration inducer and a coupling agentenhancement integrated into a guide used in conjunction with anoninvasive glucose analyzer.

SUMMARY OF THE INVENTION

A placement guide apparatus and method for use in conjunction with anoptically based noninvasive glucose analyzer is disclosed. Two couplingagents are incorporated into the guide. The first is a hydrationinducing plug used for optical coupling of the measurement apparatus tothe sampling site. The second is a fluorocarbon mixture used for opticalcoupling of the measurement apparatus to the sampling site.

The guide has a mount, an aperture defined by the mount, and an opticalcoupling apparatus, namely a hydration inducing plug. The mount has acontact surface at one end, at least a portion of the contact surfacebeing contact with a sampling site. The aperture is adapted to receivean optical probe, which is part of the optically based noninvasiveanalyzer. The hydration inducing plug is securely attached, from theaperture, to the mount at the contacting end. The outer surface of thehydration inducing plug is aligned with the mount's contact surface andis in direct contact with the sampling site. When the optical probe iscoupled into the aperture, the hydration inducing plug acts an opticalinterface between the optical probe and the sampling site. The hydrationinducing plug is made of a material or materials, such as fluoropolymer,having properties that include at least one of being near-IRtransmissive, hydrophobic, refractive index matching, and insulating.

In one embodiment, the hydration inducing plug is an evenly flat member,the edge of which is securely attached to the mount of the guide. Whenthe optical probe is coupled with the guide, both the incidental opticsand the collection optics are in direct contact with the inner surfaceof the hydration inducing plug.

In another embodiment, the hydration inducing plug includes multiplelayers. Each of the layers may have its own physical properties. Themultiple layers may be evenly or unevenly heat compressed. In an unevenheat compression case, the central area of the plug is made thinner thanthe surrounding area.

In another embodiment, there is a hole in the center of the hydrationinducing plug, so that when the optical probe is coupled with the guide,the collection optics of the optical probe is fittingly coupled into thehole and has direct contact with the sampling site, while the incidentoptics of the optical probe maintains direct contact with thesurrounding area of the hydration inducing plug. To increase detection,the hydration inducing plug may be shaped as an optical convexity. Inthat case, the incident photons travel in the air for a short distancebefore they reach the inner surface of the plug.

Yet in another embodiment, the guide contains one or more reservoirs forcontainment of an optical coupling fluid that may be near-IR inactive. Aguide incorporating at least one of these couplers allows for increasedease of use and increased in precision and accuracy of near-IR basednoninvasive glucose determinations. The modified guide allows forautomated, semi-automated, or simplified sampling associated with anear-IR based noninvasive glucose analyzer or for separate opticalanalyses that use a guide.

The hydration inducing plug, also called hydration inducer coupler,replaces an older plug that has to be manually removed between samples.The removal and replacement after sampling of the plug results inseveral issues such as: (1) time involved; (2) manually dexterity; (3)introduction of pressure transients; (4) introduction of temperaturetransients; (5) possibility of loss of removable item; and (6)possibility of introducing contaminants to the sampling site. Thehydration inducing plug according to the invention mitigates all ofthese issues.

The guide coupling fluid reservoir simplifies application of a couplingfluid. To date, application of coupling fluid to a measurement site hasbeen achieved by manually placing an externally stored fluid onto thesampling site. There are many issues related to this including: (1) timeinvolved; (2) manual dexterity requirements; (3) external storage spacerequired; (4) portability concerns such as carrying the coupling fluidfor use with a portable analyzer; (5) introduction of pressuretransients, such as bumping the sampling site when applying the couplingfluid; and (6) introduction of temperature transients, such as applyinga cold coupling fluid to the sampling site. The coupling fluid reservoirscheme according to the invention allows for automated, semi-automated,or simplified coupling fluid application that mitigates all of theseissues.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic diagram showing the front, cross-sectional viewof a piece of sampling skin, a placement guide in contact with thesampling skin, and an optical probe which has not been coupled with theguide according to the invention;

FIG. 1B is a schematic diagram showing the top view of the guide's mountand the hydration inducing plug according to the invention;

FIG. 1C is a schematic diagram showing the front, cross-sectional viewof a piece of sampling skin, a placement guide in contact with thesampling skin, and an optical probe which is coupled with the guideaccording to the invention;

FIGS. 2A-2D are schematic diagrams showing multiple layers being heatcompressed together used for the hydration inducing plug according tothe invention;

FIG. 3A is a schematic diagram showing the front, cross-sectional viewof a piece of sampling skin, a placement guide with a convex hydrationinducing plug, and an optical probe which is coupled with the guideaccording to the invention;

FIG. 3B is a schematic diagram showing the front, cross-sectional viewof a piece of sampling skin, a placement guide with an evenly flathydration inducing plug, and an optical probe which is coupled with theguide according to the invention;

FIG. 3C is a schematic diagram showing the front, cross-sectional viewof a piece of sampling skin, a placement guide with a concave hydrationinducing plug, and an optical probe which is coupled with the guideaccording to the invention;

FIG. 4A is a schematic diagram showing the front, cross-sectional viewof a piece of sampling skin, a placement guide with a hydration inducingplug and with at least one reservoir in the guide's mount, and anoptical probe which is coupled with the guide according to theinvention;

FIG. 4B is a schematic diagram showing the top view of the guide's mountwith three reservoirs and the hydration inducing plug according to theinvention; and

FIG. 4C is a schematic diagram showing the top view of the guide's mountwith a single reservoir and the hydration inducing plug according to theinvention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1A is a schematic diagram showing the front, cross-sectional viewof a piece of sampling skin, a placement guide in contact with thesampling skin, and an optical probe which has not yet been coupled withthe guide according to one embodiment of the invention. In FIG. 1A, skin101 is schematically represented in layers. These layers include thestratum corneum, epidermis, dermis, and adipose tissue, as well asunderlying structures, such as muscle. Each of these layers includesmany sub-layers and structures. The guide includes a mount 102, alsocalled a guide lock, that is semi-permanently attached to a skinsurface. The mount 102 may be in any shape, such as substantiallyrectangular, circular, oval, and polygonal. The guide includes anaperture which is defined by the mount 102. The aperture may be in anyshape, such as substantially rectangular, circular, oval, triangular,hexagonal, and polygonal. The guide may be attached for one or moresubsequent glucose determinations and is typically attached to the skinfor the period of a waking day. The guide may be attached for longerperiods of time such as days or weeks or for shorter periods of timesuch as about four or eight hours. The guide may be viewed as one-halfof a lock and key mechanism where the key aspect of the mechanism is theassociated part on the glucose analyzer, i.e. the optic probe thatcouples to the guide 103. The key may be a fiber optic, a bundle offibers, or open air optics as described in the co-pending U.S. patentapplication Ser. No. 10/349,573. Additional disclosure on the guide isprovided in Blank, et. al., supra and in the co-pending U.S. patentapplication Ser. No. 10/170,921, which is incorporated herein in theirentirety by this reference thereto.

The guide may be attached to the skin surface as in Blank, et. al.,supra and as in the co-pending T. Blank, G. Acosta, M. Mattu, M.Makarewicz, S. Monfre, A. Lorenz, T. Ruchti, Optical sampling interfacefor in-vivo measurement of tissue, U.S. patent application Ser. No.10/170,921 (filed Jun. 12, 2002). Typically a thin film double sidedadhesive is used to couple the guide to the sampling site with a holepunched into the adhesive that correlates in position to the sample siteactually probed by photons collected by the glucose analyzer. Theadhesive may be a moleskin adhesive layer. The adhesive may be used tohelp contain the coupling fluid as discussed below.

In the embodiment pictured in FIG. 1A, the guide has an additionalcomponent that fits between the skin surface and the sampling opticalprobe 103. This added component is the coupling member, which isreferred herein after as hydration inducing plug 104, although it may bereferred to alternatively as a plug, coupler, hydration inducer, orindex matching element or structure. The hydration inducing plug 104 ishere used in conjunction with a noninvasive glucose analyzer for atleast one of: (1) enhancement of hydration of the sampling site; (2)temperature control and/or stabilization of the sampling site; (3)optical coupling of the glucose analyzer to the sampling site; and (4)minimization of collected specular reflectance.

The hydration inducing plug 104 serves many of the same purposes as apreviously described separate element, herein referred to as the oldplug or traditional plug. The old plug was first introduced in Blank,et. al., supra. The old plug basically serves as a hydration inducer oraccelerator and is made of polycarbonate. As mentioned above the oldplug has many potential issues, such as requiring time and ability fromthe user and introducing the risk of error introduction in the samplingprocess through parameters, such as introduction of temperature andpressure transients at the sampling site.

The use of the hydration inducing plug 104 that is attached to the guideand that does not need to be removed and replaced between samples hasmultiple advantages. First, as the hydration inducing plug 104 is alwayspresent, it may not be lost. Second, it acts as a natural barrier tocontaminants reaching the sample site. Third, it is maintained at skintemperature by the body and does not introduce a temperature transientat the sample site as a removed plug that become cold would do whenreplaced at the sampling site. Fourth, since the hydration inducing plug104 is flexible and does not need to be replaced, the risks of pressuretransients associated with replacing the older plug in contact with thesampling site are mitigated. Fifth, as the hydration inducing plug 104is passive it does not require time to remove and replace nor does itrequire manual dexterity to do so. Sixth, external storage of a fluidand applicator devices is not required.

FIG. 1B is a schematic diagram showing the top view of the guide's mountand the hydration inducing plug. The ovals 107 represent optional cutouts on the guide surface that allow for temperature control and/or alighter guide. Associated pressure and temperature benefits are furtherdescribed in the co-pending U.S. application Ser. No. 09/954,856.

FIG. 1C is a schematic diagram showing the front, cross-sectional viewof a piece of sampling skin, a placement guide in contact with thesampling skin, and an optical probe which is coupled with the guide. Inthe embodiment presented in FIGS. 1A-1C, the hydration inducing plug 104has a hole 108 in the center that allows a collection member (optics)106 of the optic probe 103 to penetrate to the skin surface. The hole108 is used in order to minimize specular reflectance off of the skinsurface when the lock and key mechanism is a single unit. As shown inFIG. 1C, an optional spacer 109 is set between the incident member(optics) 105 and the collection member (optics) 106. The spacer 109 maybe used to block specular reflectance but may also be used to samplephotons from a larger optical depth. The hole 108 in the center may becreated by mechanical or optical means such as a laser punch.

The skin sample 101 is coupled to the glucose analyzer through the guideas pictured in FIG. 1C. The incident photons are delivered into the skinsample 101 through the incident member (optics) 105 and then through thehydration inducing plug 104. The collection member (optics) 106 forcollecting returned photons is in direct contact with the skin sample101. The path of the photons is pictured schematically to enhanceunderstanding of where the photons are traveling in the particularembodiment. Those skilled in the art will appreciate that the actual raytrace of the photons is much more complex than is schematicallypictured.

Coupler Properties

In all embodiments within this specification, the desirable propertiesof the hydration inducing plug 104 include at least one of: (1)hydrophobic; (2) insulating; (3) mechanically flexible and strong; (4)near-IR transmissive from 1100 to 1900 nm; and (5) index of refractionmatched.

Some examples of materials that fulfill all of these criteria arefluoropolymers. Fluoropolymers are available in almost any shape andthickness. For example, fluoropolymer films are available from about 25μm thick to 1 to 3 mm in thickness. Certainly, thicker layers areavailable. Particular examples of fluoropolymers include Teflon® andTeflon® AF. The term Teflon is used in this specification to represent afluoropolymer due to the wide recognition of the properties of Teflon,but many additional fluoropolymers have the characteristics describedherein.

A fluoropolymer such as Teflon is hydrophobic. As a result, Teflonplaced on the surface of the skin results in hydration of the coveredskin sample site from the deeper internal layers of skin out towards thesurface. The use of a hydrophobic barrier may result in both theincreased degree of hydration of the surface structures of the skin anda reduction in the required time to achieve a given hydration level.Both of these are important in the performance of noninvasive glucoseanalyzers as it results in an increased average depth of penetration ofthe incident photons due to fewer locations of strong index ofrefraction differences between dry tissue and air pockets. This resultsin less scattering and hence deeper average photon penetration. Further,a consistent hydration level results in more precise sampling.

Teflon is a poor thermal conductor. This means that the sampled surfacemay be insulated from environmental temperature variations. This isimportant because temperature fluxuations affect the wavelength andmagnitude of near-IR absorbance of many skin constituents such as water,protein, and glucose. These changes in optical properties have beenreported as detrimental to chemometric procedures, such as meancentering and multivariate analysis such as PCR or PLS, which arecommonly applied in near-IR based noninvasive glucose determinations.

Very thin films of Teflon are available or may be prepared that havegreat flexibility and are strong. This allows the Teflon to couplereadily to the sample site without resulting in alterations of thesampling site due to mechanical rigidness. The importance of applyingminimal physical perturbations to the sampling site has been outlined inHazen, et. al. supra and M. Makarewicz, M. Mattu, T. Blank, G. Acosta,E. Handy, W. Hay, T. Stippick, B. Richie, Method and apparatus forminimizing spectral interference due to within and between samplevariations, U.S. patent application Ser. No. 09/954,856 (filed Sep. 17,2001).

Teflon AF is greater than 90% transmissive from 400 to 2000 nm, asreported in http://www.dupont.com/teflon/af/unique.html. This allowsincident photons from the sampling probe to penetrate through thehydration inducing plug into the sampling region of the skin. As isobvious to those skilled in the art, the transmittance of the samplingphotons through the hydration barrier is critical if the hydrationbarrier is to be left in the optical path during sampling.

Refractive Index

Teflon AF has a refractive index of around 1.32 at room temperature. Therefractive index of Teflon AF has been reported as varying from 1.29 to1.316 as temperature decreases from 300 to 100° C. according to thedocumentation in http://www.dupont.com/teflon/af/unique.html. Notably,this is nearly equivalent to the refractive index of fluorocarbons suchas Fluorinert and FC-40 that have been reported to be utilized asnear-IR coupling agents in noninvasive glucose determination (discussedbelow). The refractive index and transmission characteristics of TeflonAF result in optical throughput similar to systems that utilize couplingfluids such as FC-40.

In one embodiment of the invention, the optically transparent plug maymitigate or eliminate the need for a coupling fluid. That is, the plugacts as an optical coupler based upon having a refractive index betweenthat of the skin and of the surrounding medium through which theincident photons or collection photons are traveling. For example, 2.8%of normally incident photons traveling from air with a refractive indexof 1.0 to skin with a refractive index of 1.4 is reflected. With anintermediate layer, such as Teflon AF, the percentage of reflectedphotons for the same case reduces to 1.8%. Hence, more photons maypenetrate into the sample and the resulting signal to noise mayincrease. This is exactly one of the purposes of an optical couplingfluid, such as a fluorocarbon molecule like FC-40. In this case, thehydrophobic nature of Teflon results in hydration of the interfacebetween the Teflon and skin. Because water has an index of refraction of1.33 which is between the 1.30 and 1.4 indices of Teflon AF and skin,this may further increase the percentage of incident photons penetratinginto the sample.

It is possible to construct the coupler out of more than one layer.Individual film layers of different fluoropolymer sheets are pictured inFIG. 2A. Two or more layers may be combined. Each layer may have its ownphysical properties, such as differences in refractive index.

As shown in FIG. 2B, several sheets are pressed together to remove airgaps into a composite film or composite sheet. Combining the layers in apartial vacuum can reduce trapped air bubbles, which is important whentrying to match the indices of refraction. Arranging two or more sheetsof the plastic or polymer in order of increasing or decreasingrefractive index allows a composite material to be formed that hasenhanced optical coupling abilities. For example, normal incidentphotons moving from air with an index of refraction of 1.0 to skin withan index of refraction of 1.4 results in 97.2% of the photons enteringthe skin, not accounting form surface irregularities. An intermediatecoupling layer with an index of refraction of 1.30 increases the lightthroughput to 98.2%. This means that observed light throughput in theglucose analyzer can be increased by approximately 1% using a Teflon AFlayer with an index of refraction of 1.30 between the air and the skin.Additional layers may further increase light throughput as shown inTable 1. This is calculated using the Fresnel equation.

TABLE 1 Light throughput from air to skin based upon index ofrefraction. Indices of Refraction Light Throughput Layer n/n + 1/etc . .. (Percent) 1.0/1.4 97.2 1.0/1.30/1.4 98.2 1.0/1.20/1.30/1.4 98.91.0/1.1/1.2/1.3/1.4 99.3

In FIG. 2C, the sheets of FIG. 2B are heat seated together to form athinner film than that presented in FIG. 2B. The resulting film may havemechanical advantages, such as a thinner thickness and strength. Inaddition, the refractive index of the compressed film is different thanthe uncompressed film. For example, layer 1 with an index of refractionof n₁ may have a new index of refraction n₁ as shown in FIG. 1C afterheating forming. Particularly, the index of refraction of theindependent layers may be higher than those of the original layers. Inaddition, the reaching of a glass transition temperature can formintermediate layers with intermediate refractive indices on an atomicscale. The heat seated film of multiple layers may be used when coupledto a sample, such as skin, to increase the light throughput according tothe Fresnel equation as demonstrated above and in Table 1.

In the formation of the sheets, a press may be used. The press may beheated. To reduce formation of air bubbles between layers, the press maybe under a vacuum. The press may be optically smooth to increase lightthroughput of normally incident radiation. Similarly, the press may beoptically rough if diffuse light is preferred. This may be useful forthe application of reducing the amount of light propagating through thelength and/or width of the sheet as in a light pipe or in reducingspecular reflectance. The press may be the outer dimensions of an optic.This would allow the layers to be pressed into a light directing optic.Finally, the varying thickness would allow incident light to bewavelength separated. That is, as light is passed through the material,it would be wavelength separated by refraction.

In FIG. 2D, different areas of the sheets of FIG. 2B are compressed orheat seated to varying degrees. For example, the central point of thecoupler may be heat compressed to form a thinner layer. This layer maybe the region coupling the skin to the collection fiber of FIG. 3C. Thebenefits of this are discussed below.

The stacked layers of fluoropolymer sheets discussed above may becoupled to a number of other substrates and used to increase incidentlight throughput. For example, the fluoropolymer films may be attachedto filters, longpass filter, shortpass filter, bandpass optics, lenses,optics, and/or fiber optics and used as a cheap method ofanti-reflection coating.

Configurations

In another embodiment, the hydration inducing plug may be shaped into alight directing optic. This is presented schematically in FIG. 3A. Here,incident photons are traveling through air when they reach the hydrationinducing plug 301 which has a convex inner surface. The inducing plug301 is shaped so as to direct light towards the central collectingoptic(s) 106. This may have the effect of increasing light detectionfrom a central light collection optic, such as a fiber or a light pipe.With appropriate shape to the optic in conjunction with the rest of theoptical system, the average depth of penetration of the photons may beadjusted. As described below, the guide as a whole may be a disposableitem, or be an item that is periodically removed and replaced. If thealgorithm treats acquired spectra in a fashion that incorporates a biascorrection, the precision of the optic would not have to be held to highstandards. That is, the light throughput could be adjusted for eachindividual guide by subtracting the average photon flux through guide.

In another embodiment, as shown in FIG. 3B, the hydration inducing plug302 covers the entire sampling site so that both incident photons ontothe skin and photons emerging from the skin must penetrate through thelayer. This configuration has a risk of allowing the detection ofspecularly reflected light. That is collection of light that has notpenetrated into the sample site but is reflected off of the surface ofthe skin or is reflected off of layers within the hydration inducingplug 302. It has been demonstrated that detection of significant levelsof specularly reflected light may be detrimental to a near-IR basednoninvasive glucose analyzer. It is noted that the amount of detectedspecular reflectance can be reduced by any of more collimated incidentradiation, a thinner hydration inducer, a wider spacer, or reduction ofthe numerical aperture of the collection optic(s). It is obvious tothose skilled in the art that the plug thickness and the spacer widthcoupled with the numerical aperture of the collection optic(s) andincident angle of the photons may be adjusted to minimize the degree ofcollection of spectrally reflected light.

In another embodiment as shown in FIG. 2D, the hydration inducing plug303 covers the entire sample site probed by the incident photons, butthe central area of plug is thinner than the surrounding area. In otherwords, the inner surface of the plug is concave toward the samplingskin. For example, if the plug is made of Teflon, the central areacorrelating with the collection optic(s) 106 may be heated and pressedinto a very thin layer. The dimensions of the compressed region may beon the order of 0.001 inch or 25 μm. Combined with a spacer of 10 to 300μm and the refractive index of a collection fiber with a low numericalaperture fiber such as fused silica, the degree of spectrally reflectedlight optically coupled into the collection fiber is minimal relative tothe degree of collected signal from the sample. The pressed region ofthe coupler that is in contact with the spacer may be made with a pressthat is rough to reduce the horizontal light pipe characteristics of thecoupler.

Advantages of a Coupler Integrally Coupled to the Guide

Previously, a traditional plug or older plug has been used in theplacement guide. The plug has several purposes. First, the plug isutilized to increase hydration of the sampling site. Increases inhydration may initiate in the deeper layers of the outer skin andprogress towards the outer layer of the skin. Second, the plug acts as abarrier to foreign objects such as dirt from contaminating the samplingsite. Third, the plug acts as an insulator stabilizing the sample sitetemperature.

In any of the above configurations, a hydration inducing plug of amaterial such as a fluoropolymer or Teflon, applied over the samplingsite has several advantages:

First, the older traditional plug is an object that may be misplacedwhereas the hydration inducing plug according to the invention isattached securely to the mount of the guide.

Second, a hydration induced such as a Teflon film is always in contactwith the sampling site and/or coupling fluid. This means that thelocalized pressure is constant. Removing and replacing the traditionalplug often results in small localized pressure transients, which mayadversely affect the precision of a near-IR based noninvasive glucoseanalyzer. The importance of applying minimal physical perturbations tothe sampling site has been outlined in Hazen, et. al., supra and M.Makarewicz, M. Mattu, T. Blank, G. Acosta, E. Handy, W. Hay, T.Stippick, B. Richie, Method and apparatus for minimizing spectralinterference due to within and between sample variations, U.S. patentapplication Ser. No. 09/954,856 (filed Sep. 17, 2001).

Third, the old plug is a bulky item that is quite thick. The protrusionfrom the surface of the skin makes it easy to bump or jar. This physicaljarring is transferred to the sampling site. As mentioned above, thismay be quite detrimental to the noninvasive glucose determination.

Fourth, the old plug has to be physically removed and replaced by theuser. This requires time and manual dexterity. As the hydration inducingplug according to the invention is integrally part of the guide, thisstep becomes unnecessary.

Fifth, while both the traditional plug and the new hydration inducingplug according to the invention act as an insulator, the removal of theplug away from the sampling site allows it to change temperatures. Thisresults in a localized temperature transient when replaced onto thesampling site.

Guide Reservoir Embodiments

The guide may contain one or more cavities or reservoirs in the mount ofthe guide for containing a coupling agent. FIG. 4A is a schematicdiagram showing the front, cross-sectional view of a piece of samplingskin, a placement guide with a hydration inducing plug 401 and with atleast one reservoir 402 in the guide's mount, and an optical probe whichis coupled with the guide. The coupling agent may be delivered in amanual or in an automated fashion to the sampling site. The guide cavityor reservoir may be open to the sample surface or may have channels tothe sample surface and/or sampling site. As stated above, the guide hasa lock and key mechanism that interfaces a sampling site to abioanalyzer such as near-IR based noninvasive glucose concentrationanalyzer.

Coupling Agent Properties

Index Matching: The coupling fluid itself may be any index of refractionmatching solution. However, it is preferably near-IR inactive. That isit is preferably a chlorofluorocarbon molecule or a chlorofluorocarbonpolymer. Because the chlorine in a chlorofluorocarbon is associated withtoxicity, it is preferable that the coupling fluid be a fluorocarbonmolecule, a fluorocarbon polymer, a fluorocompound, or a mixture of anyof these. Some specific examples are FC-40, FC-70, and FC-72 availablefrom 3M. The index of refraction of FC-72, FC-40, and FC-70 is 1.251,1.290, and 1.303, respectively. This is intermediate between skin with arefractive index of 1.44 and air with a refractive index of 1.0 andthus, according to Fresnel, may increase the percentage of normallyincident photons penetrating into the skin. In the case where a Teflonhydration inducing layer is used, the FC-compounds with an index ofrefraction ranging from about 1.25 to 1.31 is well matched to Teflon ACwith an index of refraction of 1.29 to 1.32. The coupling fluid mayalternatively serve the purpose of partially penetrating into the skinto provide better optical coupling more internalized layers of skin. Forexample, the fluorinert may wet the keratinocytes, displace air pockets,and generally level the rough surface.

Thermal: The reservoir(s) 402 within the guide has several thermaladvantages. First, the guide material about the reservoir acts as aninsulator to environmental conditions. For example, if the subject stepsoutside into a cold environment, there can be a delay in the cooling ofthe coupling fluid due to the insulator. An optional additionalinsulator such as a wrap or sleeve may be used in the event that theguide provides insufficient insulation. Second, the proximity of thereservoir to the skin allows for the coupling fluid to be naturallymaintained at or near the skin temperature. This is advantageous aschanges in the temperature of the sampling site may be detrimental tonear-IR based noninvasive glucose determinations. Hence, application ofcold coupling fluids to the sampling site just prior to noninvasivesampling may degrade analytical performance of a glucose analyzer bychanging the sample site temperature. In the system as presented inFIGS. 4A-4B, the movement of the coupling fluid to the sampling sitefrom the reservoir(s) 402 is along the skin surface thus maintaining thecoupling fluid temperature and resulting in minimal changes to thesampling site temperature. In the embodiment as shown in FIG. 4A, forexample, the Teflon hydration inducing plug 401 further insulates thecoupling fluid temperature during the migration.

Mechanical: It should be appreciated that the schematic of FIG. 4presents just one of a wide variety of mechanisms for the coupling agentto be delivered from the guide reservoir to the sampling site. Manyshapes and positions of the reservoir(s) may be readily designed andmany channels, tunnels, or patterns for movement of the coupling agentfrom the reservoir to the sampling site may be designed without alteringthe scope of the invention.

Optical: The intent of the photon traces in FIG. 4A is for illustrativepurposed only. It is recognized that the actual optical paths traveledare far more complex with interactions to many layers and structuresthat are not presented beyond a schematic level. For example, the Teflonspacer may be of multiple layers, have varying density with radialposition, or be shaped into optics as described above. Similarly, theskin structure and optical probe have many details and layers beyond theschematic presentation.

Delivery: The coupling fluid is directed to the sample site by at leastone of: (1) gravity; (2) diffusion; (3) a guiding channel; (4) amechanical pump; (5) manually applied pressure; and (6) anelectromechanical system such as an intelligent polymer system.

Embodiments described below may use one or more of these deliveryforces. The energy used by these systems may be provided by one or moreof a manually applied force, an internal power supply such as a battery,an external power supply, or natural forces, such as diffusion orgravity.

These delivery systems reduce chances for contamination and insureadequate delivery of the agent to the sampling site.

One embodiment of a coupling agent cavity in a guide lock and keymechanism is indicated conceptually in FIG. 4A. A cavity or reservoir402 in the guide may contain an optical coupling agent such as thosedescribed below. This system is pictured as a diffusion-based couplingagent delivery system; however other mechanisms for delivery may be usedwith this configuration. In this system, the internal reservoir ofcoupling fluid diffuses out to the sampling site. The coupling agent isguided through one or more channels to the optical sampling site. Thechannels may be in direct contact with the skin and/or may lead throughthe guide element to the sampling site. A barrier to direct the couplingagent toward the sampling site as opposed to away from the sampling sitemay be any of: (1) contact of the guide to the skin to act as a physicalbarrier; (2) a physical barrier on the guide such as a ridge thatminimally deforms the skin to form a physical barrier around thesampling site; and (3) an adhesive on the guide that circumscribes thesampling site and couples the guide to the skin around the samplingsite.

The optical coupling agent (fluid) then travels inward toward the centerof the sampling site. Optionally, a hydration inducing plug such as onedescribed above may be used. In this case, the optical coupling fluidwould preferably flow and spread between the outer surface of thehydration inducing plug and the skin surface of the sampling site.

In the embodiment pictured in FIG. 4A, an optional fluoropolymerhydration inducer is shown. This allows the optical coupling fluid to bemaintained next to the skin surface. In the configuration as presentedin FIG. 4B, three entrance channels are designed. One, two, three ormany channels may be used. In this system, containment of the couplingfluid is desirable in order to keep the fluid from merely running aroundthe sampling site. As the arrow 411 in FIG. 4B shows, moving radiallyinward, the optical coupling fluid flows from the reservoir 402, passinga non-optically sampled region 412, through a region 413 that may beused to introduce photons into the sampling skin, and finally to acentral area 414. As described above, the hydration inducing plug mayhave a hole in its center, and the collection optics is fittinglycoupled into the hole when the guide lock and key mechanism is coupledtogether. Notably, the coupling fluid reservoirs may be used without theTeflon hydration inducing plug.

Another possible configuration of such a guide with one internalreservoir or cavity for containing a coupling fluid is presented in FIG.4C. In this configuration, the single reservoir 403 is designed withinthe guide's mount. This system uses mechanical force to induce movementof the coupling fluid from the reservoir 403 to the sampling site. Forexample, the reservoir 403 within the guide may be under any of: (1) amanual press button, wherein pressing the button forces a plunger or thelike to drive the coupling fluid out of the reservoir; (2) a mechanicalpump; and (3) a thin wall blister, wherein application of force by forexample a finger causes the blister to deform physically pushing thecoupling fluid our of the reservoir. Additional driving forces asdescribed in this specification may be used to drive the coupling fluid.A barrier 404 may be used to contain the coupling fluid from thereservoir 403 within the guide. This barrier may be circular, oval, or anumber of other simple and/or complex shapes. One or more optionalbarriers 405 within the contained region force the coupling fluid toenter the center sampling area from one or more directions.

In the configurations as presented in FIG. 4B and FIG. 4C, a gravityfeed system or other driving mechanisms may be used. To enhance agravity fed system, the reservoir or reservoirs are positioned withinthe guide based upon the sampling site location and common anatomicalpositions. Sample sites include any of the arm, base of thumb, back ofwrist, volar or dorsal aspect of the forearm, and upper arm, head,torso, abdominal region, leg, thigh, and calf. The preferred samplingsites are the top of the forearm or the back of the wrist. For both ofthese anatomical sites, natural physiological positions are for the armto hang down by ones side or to rest on an armrest. This leads tological positioning of the coupling agent reservoir to be above (towardsthe elbow) the sampling site. Thus, when the arm is hanging down by theside of the subject, gravity is pulling the coupling fluid out of thereservoir nearest the elbow down towards the sampling site. Also, as thearm may rotate reservoirs may be on either side of the sampling site.Thus, with rotation of the arm, the coupling fluid may flow by gravityfrom one of the two side reservoirs towards the sampling site. While oneor more reservoirs are possible, in the preferred arrangement threereservoirs are placed around the sampling site at roughly the points ofan isosceles triangle. A single ring reservoir around the sampling siteis also possible, but is not preferred as the coupling fluid may justrun around the sampling site.

The guide's lock base, i.e. the unit including the mount together withthe hydration inducing plug and any other accessories such as theadhesive layer(s), physical guiding component(s), coupling agentreservoir(s), and coupling fluid may be a disposable. The guide unit maybe an item applied to a sampling site for the period of about one day,one waking day, or shorter period such as about two, four, or eighthours. For professional use, such as use in conjunction with a glucosetolerance test, the guide unit may be attached for a fraction of a daysuch as for two, four, or six hours. Alternatively, the guide unit as awhole may be an apparatus that is periodically removed from the samplingsite and later replaced, perhaps with new adhesives.

The optical unit, i.e. the optical probe, coupling into the guide basemay be created in a number of optical configurations. For example, fiberoptics may be used to deliver light to the sample and/or to collectlight from the sample. Notably, other optical configurations may beemployed. For example, hollow tubes may be used for guiding theexcitation and/or collected photons. In addition, photons may betraveling through air rather than through a fiber. This is particularlytrue for the incident photons.

People come in various dimensions in terms of physical length or widthof a body part and curvature of that body part. Accordingly, guides maybe used that have varying dimension, and curvatures. Guides may besupplied in large, medium, or small sizes each with a varying radius ofcurvature. Existing guides range from approximately 0.5 to 1.5 inches indiameter. Larger guides are readily developed. It is desirable tomanufacture smaller guides as the noninvasive glucose analyzer isengineered to smaller sizes.

A number of individual elements are presented in this invention. It isimportant to note that many of these elements or features may be used inconjunction with one another. The invention is intended to employ atleast one of: a plug, a multi-layer coupling hydration inducing plug, acoupling layer that is pressed into a non-flat sheet, a plug with ahole, an optically shaped coupling plug, a coupling fluid reservoir, andchannels for diffusion or manual control of delivery of a couplingfluid.

In view of the different possible embodiments to which the principle ofthis invention may be applied, it should be recognized that thepreferred embodiments described herein with respect to the drawings aremeant to be illustrative only and should not be taken as limiting thescope of the invention. One skilled in the art will readily appreciatethat other applications may be substituted for those set forth hereinwithout departing from the spirit and scope of the invention.

Accordingly, the invention should only be limited by the Claims includedbelow.

1. A placement guide used for coupling of an optical probe of anoptically based noninvasive glucose concentration analyzer to a samplesite of a skin sample, said optical probe comprising at least oneoptical incident member for delivering incident photons into the samplesite and an optical collection member for collecting photons emergingfrom the sample site, said guide comprising: a mount having a contactsurface at one end; an aperture, defined by said mount, which is adaptedto receive said optical probe during use, wherein an area defined bysaid aperture comprises the sample site; and a hydration inducing plugcovering said aperture, wherein an outer surface of said hydrationinducing plug aligns with said contact surface of said mount, said outersurface adapted to be in proximate contact with the sample site duringuse; wherein said hydration inducing plug acts as an optical interfacebetween said optical probe and the sample site when said optical probeis coupled into said aperture, and wherein said hydration inducing plughas an aperture formed in its center thereof, wherein upon said opticalprobe being coupled with said guide, said optical collection member ofsaid optical probe is coupled into said aperture and is adapted to havedirect contact with the sample site, while said optical incident memberof said optical probe is adapted to maintain direct contact with asurrounding area of said hydration inducing plug.
 2. The guide of claim1, wherein said hydration inducing plug comprises a hydrophobicmaterial.
 3. The guide of claim 1, wherein said hydration inducing plugcomprises a fluoropolymer material.
 4. The guide of claim 1, whereinsaid hydration inducing plug comprises multiple layers.
 5. The guide ofclaim 4, wherein each of said layers comprises its own physicalproperties.
 6. The guide of claim 1, wherein said mount comprises aplurality of channels for delivery of a coupling fluid, each of saidchannels being connected to a coupling fluid reservoir, said couplingfluid spreading between the outer surface of said hydration inducingplug and the skin surface of the sample site during use.
 7. The guide ofclaim 1, wherein said hydration inducing plug comprises a hydrophobicnear-IR transmissive material from 1100 to 1900 nm.
 8. The guide ofclaim 1, wherein said hydration inducing plug comprises a material indexof refraction matched to said contact surface of said mount.